This application is a 371 of PCT/SE00/02064 filed Dec. 19, 2000, now WO 01/47893 Jul. 5, 2000.
This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.
Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with xe2x80x9ctraditionalxe2x80x9d antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class m or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of noncardiac drugs such as phenotiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 665 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). 3-Azabicyclo[3.2.1]octane compounds are neither disclosed nor suggested in any of these documents.
Compounds based on 3-azabicyclo[3.2.1]octanes are known for use in a variety of other medical applications including serotonin antagonism (as described in EP 212 802 and EP 645 391), neurokinin-I receptor antagonism (as described in WO 98/18788), nitric oxide synthase inhibition (as described in WO 97/36871) and analgesia (as described in Rico, B, et al., J. Heterocycl. Chem. 31(2), 313-318 (1994)). None of these documents either disclose or suggest the use of 3-azabicyclo[3.2.1]octane-based compounds as antiarrhythmic agents.
We have surprisingly found that a novel group of 3-azabicyclo[3.2.1]octane-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.
According to the invention there is provided compounds of formula I, 
wherein
the wavy bond represents optional endo- or exo-stereochemistry;
one of R1 and R2 represents R1a and the other represents a fragment of the formula Ia, 
R1a represents C1-12 alkyl (optionally substituted and/or terminated by one or more groups selected from halo, cyano, nitro, aryl, Het1, xe2x80x94C(O)R7a, xe2x80x94OR7b, xe2x80x94N(R8)R7c, xe2x80x94C(O)XR9, xe2x80x94C(O)N(R10)R7d and xe2x80x94S(O)2R11), Het2, xe2x80x94C(O)R7a, xe2x80x94C(O)XR9, xe2x80x94C(O)N(R10)R7d or xe2x80x94S(O)2R11;
R7a to R7d independently represent, at each occurrence when used herein, H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, C1-6alkoxy, halo, cyano, nitro, aryl, Het3 and xe2x80x94NHC(O)R12), aryl or Het4, or R7d, together with R10, represents C3-6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C1-3 alkyl groups);
R12 represents H, C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, cyano, aryl and xe2x80x94NHC(O)R13) or aryl;
R13 represents H, C1-4 alkyl or aryl;
R8 represents H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl, xe2x80x94C(O)R14a or xe2x80x94C(O)OR14b;
R14a and R14b represent C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl) or aryl, or R14a represents H;
X represents O or S;
R9 represents, at each occurrence when used herein, C1-12 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, aryl, C1-4 alkoxy, xe2x80x94SO2R15 and Het5);
R15 represents C1-6 alkyl or aryl;
R10 represents, at each occurrence when used herein, H, C1-12 alkyl, C1-6 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro, C1-4, alkyl and C1-4 alkoxy), xe2x80x94D-aryl, xe2x80x94D-aryloxy, xe2x80x94Dxe2x80x94Het6, xe2x80x94Dxe2x80x94N(H)C(O)R16a, xe2x80x94Dxe2x80x94S(O)2R17a, xe2x80x94Dxe2x80x94C(O)R16b, xe2x80x94Dxe2x80x94C(O)OR17b, xe2x80x94Dxe2x80x94C(O)N(R16c)R16d, or R10, together with R7d, represents C3-4 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted.by one or more C1-3 alkyl groups);
R16a to R16d independently represent H, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl,) or R16c and R16d together represent C3-6 alkylene;
R17a and R17b independently represent C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl) or aryl;
D represents a direct bond or C1-6 alkylene;
R11 represents, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, nitro and aryl), aryl or Het7;
R4 represents H, halo, C1-6 alkyl, xe2x80x94OR18, xe2x80x94Exe2x80x94N(R19)R20 OR together with
R5, represents xe2x95x90O;
R5 represents H, C1-6 alkyl or, together with R4, represents xe2x95x90O;
R18 represents H, C1-6 alkyl, xe2x80x94E-aryl, xe2x80x94Exe2x80x94Het8, xe2x80x94C(O)R21a, xe2x80x94C(O)OR21b or xe2x80x94C(O)N(R22a)R22b;
R19 represents H, C1-6 alkyl, xe2x80x94E-aryl, xe2x80x94Exe2x80x94Het8, xe2x80x94C(O)R21a, xe2x80x94C(O)OR21b, xe2x80x94S(O))2R21c, xe2x80x94[C(O)]pN(R22a)R22b or xe2x80x94C(NH)NH2;
R20 represents H, C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94C(O)R21d;
R21a to R21d independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het9), aryl, Het10, or R21a and R21d independently represent H;
R22d and R22b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het11), aryl, Het12, or together represent C3-6 alkylene, optionally interrupted by an O atom;
E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
p represents 1 or 2;
Het1 to Het12 independently represent, at each occurrence when used herein, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from xe2x80x94OH, oxo, halo, cyano, nitro, C1-6 alkyl, C1-6 alkoxy aryl, aryloxy, xe2x80x94N(R23a)R23b, xe2x80x94C(O)R23c, xe2x80x94C(O)OR23d, xe2x80x94C(O)N(R23e)R23f, xe2x80x94N(R23g)C(O)R23h and xe2x80x94N(R23i)S(O)2R23j;
R23a to R23j independently represent C1-6 alkyl, aryl or R23a to R23i independently represent H;
A represents a direct bond, xe2x80x94Jxe2x80x94, xe2x80x94Jxe2x80x94N(R24)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94 (in which latter two groups, N(R24)xe2x80x94 or Oxe2x80x94 is attached to the carbon atom bearing R4 and R5);
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(R25)xe2x80x94, xe2x80x94N(R25)xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94S(O)11xe2x80x94, xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R4 and R5), xe2x80x94N(R25)C(O)Oxe2x80x94Zxe2x80x94, (in which latter group, xe2x80x94N(R25) is attached to the carbon atom bearing R9 and R10) or xe2x80x94C(O)N(R25)xe2x80x94 (in which latter group, xe2x80x94C(O) is attached to the carbon atom bearing R4 and R5);
J represents C1-6 alkylene optionally substituted by one or more substituents selected from xe2x80x94OH, halo and amino;
Z represents a direct bond or C1-4 alkylene;
R24 and R25 independently represent H or C1-6 alkyl;
G represents CH or N;
R6 represents one or more optional substituents selected from xe2x80x94OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by xe2x80x94N(H)C(O)OR26a), C1-6 alkoxy Nxe2x80x94, xe2x80x94N(R27a)R27b, xe2x80x94C(O)R27c, xe2x80x94C(O)OR27d, xe2x80x94C(O)N(R)R27e)R27f, xe2x80x94N(R27g)C(O)R27h, xe2x80x94N(R27i)C(O)N(R27j)R27k, xe2x80x94N(R27m)S(O)2R26b, xe2x80x94S(O)nR26c, and/or xe2x80x94OS(O)2R26d;
R26a to R26d independently represent C1-6 alkyl;
R27a to R27m independently represent H or C1-6 alkyl;
n represents, at each occurrence, 0, 1 or 2; and
Ra to Rh and R3 independently represent H or C1-4 alkyl;
wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
or a pharmaceutically acceptable derivative thereof;
provided that
(a) when A represents xe2x80x94Jxe2x80x94N(R24)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94, then:
(i) J does not represent C1 alkylene; and
(ii) B does not represent xe2x80x94N(R25)xe2x80x94, xe2x80x94N(R25)xe2x80x94Zxe2x80x94 (in which latter group N(R25) is attached to the carbon atom bearing R4 and R5), xe2x80x94S(O)nxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R25)C(O)Oxe2x80x94Zxe2x80x94 when R4 and R5 do not together represent xe2x95x90O;
(b) when R4 represents xe2x80x94OR18 or xe2x80x94N(R19)(R20), then:
(i) A does not represent xe2x80x94Jxe2x80x94N(R24)xe2x80x94 or xe2x80x94Jxe2x80x94Oxe2x80x94; and
(ii) B does not represent xe2x80x94N(R25)xe2x80x94, xe2x80x94N(R25)xe2x80x94Zxe2x80x94 (in which latter group N(R25) is attached to the carbon atom bearing R4 and R5), xe2x80x94S(O)nxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R25)C(O)Oxe2x80x94Zxe2x80x94;
(c) when A represents a direct bond, then R4 and R5 do not together represent xe2x95x90O; and
(d) the compound is not: (xc2x1) (8xcex2)-4-amino-5-chloro-2-methoxy-N-(3-benzyl-3-azabicyclo-[3.2.1]oct-8-yl)benzamide; (S)-N-(3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide; or (S)-N-(3-benzyl-3-azabicyclo[3.2.1]oct-8-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyl)oxybenzamide hydrochloride;
which compounds are referred to hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
Unless otherwise specified, alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may also be substituted by one or more halo, and especially fluoro, atoms.
Unless otherwise specified, alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkylene groups may also be substituted by one or more halo atoms.
The term xe2x80x9carylxe2x80x9d, when used herein, includes C6-10 aryl groups such as phenyl, naphthyl and the like. The term xe2x80x9caryloxyxe2x80x9d, when used herein includes C6-10 aryloxy groups such as phenoxy, naphthoxy and the like. For the avoidance of doubt, aryloxy groups referred to herein are attached to the rest of the molecule via the O-atom of the oxy-group. Unless otherwise specified, aryl and aryloxy groups may be substituted by one or more substituents including xe2x80x94OH, halo, Het1, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, N(R27a)R27b, xe2x80x94C(O)R27c, xe2x80x94C(O)OR27d, xe2x80x94C(O)N(R27e)R27f, xe2x80x94N(R27g)C(O)R27h, xe2x80x94N(R27m)S(O)2R26b, xe2x80x94S(O)nR26c, and/or xe2x80x94OS(O)2R26d (wherein Het1, R26b to R26d, R27a to R27m and n are as hereinbefore defined). When substituted, aryl and aryloxy groups are preferably substituted by between one and three substituents. When aryl is substituted by one or more Het1 group(s), any aryl group(s) that said Het1 group(s) may be substituted with may not itself (themselves) be substituted by any Het1 group(s).
The term xe2x80x9chaloxe2x80x9d, when used herein, includes fluoro, chloro, bromo and iodo. Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) groups that may be mentioned include those containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) groups may be fully saturated, wholly aromatic, partly aromatic and/or bicyclic in character. Heterocyclic groups that may be mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl, imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl, maleimido, morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thienyl, thiochromanyl, triazolyl and the like. Values of Het1 that may be mentioned include maleimido and piperazinyl. Values of Het2 that may be mentioned include thiazolyl. Values of Het that may be mentioned include hydantoinyl. Values of Het4 that may be mentioned include benzodioxanyl, benzofurazanyl, pyrazolyl and pyrrolyl. Values of Het5 that may be mentioned include morpholinyl, piperazinyl and pyridinyl. Values of Het6 that may be mentioned include isoxazolyl and tetrahydropyranyl. Values of Het7 that may be mentioned include imidazolyl, pyrazolyl, 3-sulfolenyl and thiazolyl. Substituents on Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) groups may be via any atom in the ring system including (where appropriate) a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) groups may also be in the Nxe2x80x94 or S-oxidised form.
Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the 3-azabicyclo[3.2.1]octane or (when G represents N) pyridyl nitrogens, C1-4alkyl quaternary ammonium salts and N-oxides, provided that when a N-oxide is present:
(a) no Het (Het1, Het2, Het3, Het4, Het5, Het6, Het7, Het8, Het9, Het10, Het11 and Het12) group contains an unoxidised S-atom; and/or
(b) n does not represent 0 when B represents xe2x80x94Zxe2x80x94S(O)nxe2x80x94.
The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
According to a further aspect of the invention, there is provided compounds of formula I as hereinbefore defined with the additional proviso that when Het1 or Het4 represents piperazin-1-yl, then the piperazinyl group does not bear a 3,4-dichlorophenyl substituent.
According to a further aspect of the invention, there is provided compounds of formula I, as hereinbefore defined, but without proviso (d) and with the additional provisos that:
(i) when R1 represents a fragment of formula Ia in which A represents J, B represents Z, and R4 and R5 represent H or C1-6 alkyl; then R2 does not represent C1-10 alkyl substituted by Het1 or xe2x80x94C(O)Het4 (wherein Het1 or Het4 represents homopiperazin-1-yl, piperazin-1-yl or 1-imidazolidinyl, which homopiperazinyl, piperazinyl or imidazolidinyl group is substituted in the 4-, 4- or 3-position (respectively) by xe2x80x94C(O)R23c (in which R23c represents aryl) and (at one of the ring C-atoms) by aryl, and which homopiperazinyl, piperazinyl or imidazolidinyl group is further optionally substituted by C1-6 alkyl), and which C1-10 alkyl group is further optionally substituted by one substituent selected from optionally substituted phenyl, cyano, xe2x80x94OR7b, xe2x80x94N(R8)R7c, xe2x80x94C(O)OR9, xe2x80x94C(O)N(R10)R7d (wherein R7b, R7c, R7d, R9 and R10 represent H, C1-6 alkyl or optionally substituted phenyl), imidazolyl or optionally substituted indolyl;
(ii) when Ra to Rh and R3 all represent H; and R1 represents a fragment of formula Ia in which the group xe2x80x94Axe2x80x94C(R4)(R5)xe2x80x94Bxe2x80x94 represents C1-3 alkylene, G represents CH and R6 is absent; then R2 does not represent xe2x80x94C(O)R7a, wherein R7a represents phenyl substituted in the 2-position by C3-6 alkynyloxy (optionally interrupted by oxygen), in the 4-position by xe2x80x94N(R27a)R27b or xe2x80x94N(H)C(O)R27h (wherein R27h represents C1-6 alkyl), and in the 5-position by halo; and
(iii) when R3 represents H; and R1 represents a fragment of formula Ia in which the group xe2x80x94Axe2x80x94C(R4)(R5)xe2x80x94Bxe2x80x94 represents C1-2 alkylene, G represents CH and R6 represents one or two substituents selected from C1-6 alkyl (optionally interrupted by oxygen), C1-4 alkoxy, CF3, halo, nitro, xe2x80x94C(O)OH or xe2x80x94C(O)Oxe2x80x94C1-6 alkyl); then R2 does not represent xe2x80x94C(O)R7a, wherein R7a represents phenyl substituted in the 2-position by C1-6 alkoxy, in the 4-position by xe2x80x94NH2 or xe2x80x94N(H)C(O)R27h (wherein R27h represents C1-6 alkyl), and in the 5-position by halo or xe2x80x94SR26c.
Abbreviations are listed at the end of this specification.
Preferred compounds of the invention include those in which:
R1a represents C1-8 alkyl (optionally substituted and/or terminated by one or more groups selected from halo, optionally substituted aryl, Het1, xe2x80x94C(O)R7a, xe2x80x94OR7b, xe2x80x94N(R8)R7c, xe2x80x94C(O)XR9, xe2x80x94C(O)N(R10)R7d and xe2x80x94S(O)2R11), Het2, xe2x80x94C(O)R7a, xe2x80x94C(O)XR9, xe2x80x94C(O)N(R10)R7d or xe2x80x94S(O)2R11;
R7a to R7d independently represent, at each occurrence, H, C1-5 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, C1-4 alkoxy, halo, cyano, optionally substituted aryl, Het3 and xe2x80x94NHC(O)R12), optionally substituted aryl or Het4, or R7d, together with R10, represents C3-6 alkylene;
R12 represents C1-3 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and xe2x80x94NHC(O)R13) or optionally substituted aryl;
R13 represents C1-3 alkyl or aryl;
R8 represents H, C1-4 alkyl (optionally substituted and/or terminated by optionally substituted aryl), optionally substituted aryl, xe2x80x94C(O)R14a, or xe2x80x94C(O) OR14b;
R14a and R14b represent C1-4 alkyl (optionally substituted and/or terminated by aryl) or aryl;
R9 represents, at each occurrence, C1-8 alkyl (optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo, cyano, optionally substituted aryl, C1-4 alkoxy, xe2x80x94SO2R15 and Het5);
R15 represents C1-4 alkyl or aryl;
R10 represents, at each occurrence, H, C1-8 alkyl, C1-4 alkoxy (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, halo and C1-4 alkoxy), xe2x80x94D-(optionally substituted aryl), xe2x80x94D-aryloxy, xe2x80x94D-Het6, xe2x80x94Dxe2x80x94S(O)2R17a, or R10, together with R7d, represents C3-6 alkylene;
R17a represents C1-4 alkyl or optionally substituted aryl;
D represents a direct bond or C1-3 alkylene;
R11 represents, at each occurrence, C1-5 alkyl (optionally substituted and/or terminated by one or more halo atoms), optionally substituted aryl or Het7;
R4 represents H, halo, C1-2 alkyl, xe2x80x94OR18 or xe2x80x94Exe2x80x94N(R19)R20;
R5 represents H, or C1-2 alkyl;
R18 represents H, C1-4 alkyl, xe2x80x94E-(optionally substituted aryl) or xe2x80x94Exe2x80x94Het8;
R19 represents H, C1-4 alkyl, xe2x80x94E-aryl, xe2x80x94Exe2x80x94Het8, xe2x80x94C(O)R21a or xe2x80x94C(O)OR21b;
R20 represents H, C1-4 alkyl or xe2x80x94E-aryl;
R21a and R21b independently represent C1-4 alkyl (optionally substituted and/or terminated by one or more substituents selected from halo and aryl) or aryl;
E represents, at each occurrence, a direct bond or C1-2 alkylene;
Het1 to Het8 independently represent, at each occurrence, fully saturated, wholly aromatic, partly aromatic and/or bicyclic five- to twelve-membered heterocyclic groups containing between one and four heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from oxo, halo, cyano, C1-5 alkyl, C1-4 alkoxy, xe2x80x94N(R23a)R23b, xe2x80x94C(O)R23c, xe2x80x94C(O)OR23d, xe2x80x94C(O)N(R23e)R23f, and xe2x80x94N(R23g)C(O)R23h;
R23a to R23h independently represent H or C1-3 alkyl;
A represents a direct bond or xe2x80x94Jxe2x80x94;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(R25)xe2x80x94, xe2x80x94Zxe2x80x94S(O)nxe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter three groups, Z is attached to the carbon atom bearing R4 and R5);
J represents C1-5 alkylene optionally substituted by one or more substituents selected from xe2x80x94OH, halo and amino;
Z represents a direct bond or C1-3 alkylene;
n represents 0 or 2;
R25 represents H or C1-4 alkyl;
G represents CH;
R6 represents one or more optional substituents selected from xe2x80x94OH, cyano, halo, nitro, C1-3 alkyl (optionally terminated by xe2x80x94N(H)C(O)OR26a) and C1-4 alkoxy;
R26a represents C1-4 alkyl;
R3 represents H or C1-2 alkyl;
Ra to Rh all represent H.
More preferred compounds of the invention include those in which:
R1a represents linear, branched or part cyclic/acyclic C1-6 alkyl (which alkyl group is (i) optionally interrupted by one or more oxygen atoms; and/or (ii) optionally substituted and/or terminated by one or more groups selected from phenyl (optionally substituted by one or more substituents selected from halo and methoxy), Het1 (optionally substituted by xe2x80x94C(O)R23c), xe2x80x94C(O)R7a, xe2x80x94OR7b, xe2x80x94C(O)N(H)R10 and xe2x80x94S(O)2R11), Het2, xe2x80x94C(O)R7a, xe2x80x94C(O)OR9, xe2x80x94C(O)N(H)R10 or xe2x80x94S(O)2R11;
R7a and R7b independently represent, at each occurrence, H, linear or branched C1-5 alkyl (which alkyl group is (i) optionally unsaturated; and/or (ii) optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, C1-2 alkoxy, Het3 and xe2x80x94NHC(O)R12), phenyl (optionally substituted by halo or methoxy) or Het4 (optionally substituted by C1-4 alkyl);
R12 represents C1-2 alkyl (optionally substituted and/or terminated by xe2x80x94NHC(O)R13);
R13 represents C1-2alkyl;
R9 represents, at each occurrence, linear, branched or part cyclic/acyclic C1-6 alkyl (which alkyl group is (i) optionally unsaturated; (ii) optionally interrupted by one or more oxygen atoms; and/or (iii) optionally substituted and/or terminated by one or more substituents selected from xe2x80x94OH, cyano, C1-2 alkoxy, xe2x80x94SO2R15 and Het5 (optionally substituted by xe2x80x94C(O)R23c));
R15 represents C1-2 alkyl;
R10 represents, at each occurrence, H, linear, branched or part cyclic/acyclic C1-7 alkyl, (which alkyl group is (i) optionally interrupted by one or more oxygen atoms; and/or (ii) optionally substituted and/or terminated by C1-2 alkoxy), phenyl (optionally substituted by one or more substituents selected from halo, methoxy, Het1 and SR26c), Het6 (optionally substituted by one or more C1-2 alkyl groups) or xe2x80x94S(O)2R17a;
R26c represents C1-2 alkyl optionally substituted by one or more halo atoms;
R17a represents phenyl (optionally substituted by C1-2 alkyl);
R11 represents, at each occurrence, linear, branched or part cyclic/acyclic C1-5 alkyl, phenyl (optionally substituted by one or more substituents selected from nitro, methoxy and N(H)C(O)R27h) or Het7 (optionally substituted by one or more substituents selected from halo, C1-2 alkyl and N(H)C(O)R23h);
R4 represents H, xe2x80x94OR18 or xe2x80x94N(H)R19;
R5 represents H;
R18 represents H or phenyl (optionally substituted by one or more substituents selected from OH and methoxy);
R19 represents H or xe2x80x94C(O)OR21b;
R21b represents C1-2 alkyl;
Het1 to Het8 independently represent, at each occurrence, fully saturated, wholly aromatic, partly aromatic and/or bicyclic five- to twelve-membered heterocyclic groups containing between one and four heteroatoms selected from oxygen, nitrogen and/or sulfur;
R23c, R23h and R27h independently represent, at each occurrence, C1-2 alkyl;
A represents a direct bond or xe2x80x94Jxe2x80x94;
B represents xe2x80x94Zxe2x80x94, xe2x80x94Zxe2x80x94N(H)xe2x80x94, xe2x80x94Zxe2x80x94SO2xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter three groups, Z is attached to the carbon atom bearing R4 and R5);
J represents C1-3 alkylene optionally substituted by xe2x80x94OH or amino;
Z represents a direct bond or C1-2 alkylene;
R6 represents one or two cyano groups;
R3 represents H or methyl.
Particularly preferred compounds of the invention include those in which:
R1a represents xe2x80x94C(O)R7a, xe2x80x94C(O)N(H)R10 or xe2x80x94S(O)2R11;
R10 represents linear, branched or part cyclic/acyclic C1-5 alkyl, (which alkyl group is optionally interrupted by one or more oxygen atoms);
R4 represents H, xe2x80x94OH or xe2x80x94NH2;
A represents a direct bond or xe2x80x94Jxe2x80x94;
B represents xe2x80x94Zxe2x80x94N(H)xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which latter two groups, Z is attached to the carbon atom bearing R4 and R5);
J represents C1-3 alkylene;
R6 represents a cyano group in the position para to where B is attached;
R3 represents methyl.
Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter.
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reaction of a compound of formula IIA or IIB, 
wherein R1, R2, R3 and Ra to Rh are as hereinbefore defined, with a compound of formula III,
xe2x80x83R28xe2x80x94L1xe2x80x83xe2x80x83III
wherein R28 represents either R1 or R2 (as appropriate), L1 represents a leaving group such as halo, alkanesulfonate, perfluoroalkanesulfonate, arenesulfonate, xe2x80x94OC(O)XR9, imidazole or R29Oxe2x80x94 (wherein R29 represents, for example, C1-10 alkyl or azyl, which groups are optionally substituted by one or more halo or nitro groups) and R1, R2 and R9 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, THF, toluene or mixtures thereof);
(b) for compounds of formula I in which R1 or R2 (as appropriate) represents xe2x80x94C(O)XR9 or xe2x80x94C(O)N(R10)R7d, reaction of a compound of formula IVA or IVB, 
wherein R3, Ra to Rh and L1 are as hereinbefore defined and R1 and R2 represent a fragment of formula Ia, as hereinbefore defined, with a compound of formula V,
R30xe2x80x94Hxe2x80x83xe2x80x83V
wherein R30 represents xe2x80x94XR9 or xe2x80x94N(R10)R7d and R7d, R9, R10 and X are as hereinbefore defined, for example under conditions described hereinbefore (process step (a));
(c) for compounds of formula I in which R1 or R2 (as appropriate) represents xe2x80x94C(O)N(H)R10, reaction of a compound of formula IIA or IIB (as appropriate), as hereinbefore defined (except that R1 or R2 (as appropriate) does not represent R1a), with a compound of formula VI,
R10xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83VI
wherein R10 is as hereinbefore defined, for example at between 0xc2x0 C. and reflux temperature in the presence of an appropriate organic solvent (e.g. dichloromethane), or via solid phase synthesis under conditions known to those skilled in the art;
(d) for compounds of formula I in which R1 or R2 (as appropriate) represents a fragment of formula Ia in which A represents CH2 and R4 represents xe2x80x94OH or xe2x80x94N(H)R19, reaction of a compound of formula IIA or IIB, as hereinbefore defined (except that R1 or R2 (as appropriate) does not represent a fragment of formula Ia), with a compound of formula VII, 
wherein Y represents O or N(R19) and R5, R6, R19, B and G are as hereinbefore defined, for example at elevated temperature (e.g. 60xc2x0 C. to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water);
(e) for compounds of formula I in which, in the fragment of formula Ia, B represents xe2x80x94Zxe2x80x94Oxe2x80x94, reaction of a compound of formula VIIIA or VIIIB, 
wherein R3, R4, R Ra to Rh, A and Z are as hereinbefore defined, and R1 and R2 (as appropriate) are as hereinbefore defined (except that, in each case, they do not represent a fragment of formula Ia), with a compound of formula IX, 
wherein R6 and G are as hereinbefore defined, for example under Mitsunobu-type conditions e.g. at between ambient (e.g. 25xc2x0 C.) and reflux temperature in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), an azodicarboxylate derivative (e.g. diethylazodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine) and an appropriate organic solvent (e.g. dichloromethane or toluene);
(f) for compounds of formula I in which G represents N and B represents xe2x80x94Zxe2x80x94Oxe2x80x94, reaction of a compound of formula VIIIA or VIIIB, as hereinbefore defined, with a compound of formula X, 
wherein L2 represents a leaving group such as halo, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate, and R6 is as hereinbefore defined, for example at between 10xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. sodium hydride) and an appropriate solvent (e.g. N,N-dimethylformamide);
(g) for compounds of formula I in which R4 represents xe2x80x94OR18, in which R18 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94Exe2x80x94Het8, reaction of a corresponding compound of formula I in which R4 represents OH with a compound of formula X),
R18aOHxe2x80x83xe2x80x83XI
wherein R18a represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94Exe2x80x94Het8, and E and Het8 are as hereinbefore defined, for example under Mitsunobu-type conditions (e.g. as described hereinbefore in process step (e));
(h) for compounds of formula I in which R4 represents xe2x80x94OR18, in which R18 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94Exe2x80x94Het8, reaction of a compound of formula XIIA or XIIB, 
wherein R1 or R2 (as appropriate) represents R7a, and R1a, R3, R5, R6, Ra to Rh, A, B, G and L2 are as hereinbefore defined, with a compound of formula XI, as hereinbefore defined, for example at between ambient (e.g. 25xc2x0 C.) and reflux temperature, under Williamson-type conditions (i.e. in the presence of an appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxide or N,Nimethylformamide)) (the skilled person will appreciate that certain compounds of formula XIIA and XIIB (e.g. those in which L2 represents halo) may also be regarded as compounds of formula I as hereinbefore defined);
(i) for compounds of formula I in which R4 represents xe2x80x94Exe2x80x94NH2, reduction of a compound of formula XIIIA or XIIIB, 
wherein R1 or R2 (as appropriate) represents R1a, and R1a, R3, R5, R6, Ra to Rh, A, B, E and G are as hereinbefore defined, for example by hydrogenation at a suitable pressure in the presence of a suitable catalyst (e.g. palladium on carbon) and an appropriate solvent (e.g. a water-ethanol mixture);
(j) for compounds of formula I in which R4 represents xe2x80x94Exe2x80x94N(R19)R20, wherein R19 represents C1-6 alkyl, xe2x80x94E-aryl xe2x80x94Exe2x80x94Het8, xe2x80x94C(O)R21a, C(O)OR21b, xe2x80x94S(O)2R21c or xe2x80x94C(O)N (R22a)R22b, reaction of a corresponding compound of formula I in which R4 represents xe2x80x94Exe2x80x94N(H)R20 with a compound of formula XIV,
R19axe2x80x94L1xe2x80x83xe2x80x83XIV
wherein R19a represents C1-6 alkyl, xe2x80x94E-aryl xe2x80x94Exe2x80x94Het8, xe2x80x94C(O)R21a, xe2x80x94C(O)OR21b, xe2x80x94S(O)2R21c or xe2x80x94C(O)N(R22a)R22b , and R21a, R21b, R21c , R22a, R22b, Het8, E and L1 are as hereinbefore defined, for example under conditions described hereinbefore (process step (a));
(k) for compounds of formula I in which R4 represents xe2x80x94Exe2x80x94N(R20)C(O)N(H)R22a, reaction of a corresponding compound of formula I in which R4 represents xe2x80x94Exe2x80x94N(H)R20 with a compound of formula XV,
R22axe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83XV
wherein R22a is as hereinbefore defined, for example under conditions described hereinbefore (process step (c));
(I) for compounds of formula I in which R4 represents xe2x80x94Exe2x80x94N(H)[C(O)]2NH2, reaction of a corresponding compound of formula I in which R4 represents xe2x80x94Exe2x80x94NH2 with oxalic acid diamide, for example at between xe2x88x9210 and 25xc2x0 C. in the presence of a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), an appropriate activating agent (e.g. 1-hydroxybenzotriazole), a suitable base (e.g. triethylamine) and a reaction-inert solvent (e.g. N,N-dimethylformamide);
(m) for compounds of formula I in which R4 represents xe2x80x94Exe2x80x94N(H)C(NH)NH2, reaction of a corresponding compound of formula I in which R4 represents xe2x80x94Exe2x80x94NH2 with a compound of formula XVI,
R29Oxe2x80x94C(xe2x95x90NH)NH2xe2x80x83xe2x80x83XVI
or an N-protected derivative thereof, wherein R29 is as hereinbefore defined, for example at between room and reflux temperature, optionally in the presence of a suitable solvent (e.g. toluene) and/or an appropriate acidic catalyst (e.g. acetic acid at, for example, 10 mol %);
(n) for compounds of formula I in which R4 represents xe2x80x94OR18, in which R18 represents xe2x80x94C(O)R21a, xe2x80x94C(O)OR21b or xe2x80x94C(O)N(R22a)R22b, reaction of a corresponding compound of formula I in which R4 represents xe2x80x94OH with a compound of formula XVII,
R18bxe2x80x94L3xe2x80x83xe2x80x83XVII
wherein R18b represents xe2x80x94C(O)R21a, xe2x80x94C(O)OR21b or xe2x80x94C(O)N(R22a)R22b, L3 represents a leaving group such as halo, p-nitrophenoxy, xe2x80x94OC(O)R21a, xe2x80x94OC(O)OR21b, xe2x80x94OH or imidazole and R21a, R21b, R22a and R22b are as hereinbefore defined, for example at between xe2x88x9210xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. triethylamine, pyridine or potassium carbonate), an appropriate organic solvent (e.g. THF, dichloromethane or acetonitrile) and (where appropriate) a suitable coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide);
(o) for compounds of formula I in which R4 represents H or xe2x80x94OH and R5 represents H, reduction of a corresponding compound of formula I in which R4 and R5 together represent xe2x95x90O, in the presence of a suitable reducing agent and under appropriate reaction conditions; for example, for formation of compounds of formula I in which R4 represents OH, reduction may be performed under mild reaction conditions in the presence of e.g. sodium borohydride and an appropriate organic solvent (e.g. THF); and for formation of compounds of formula I in which R4 represents H, reduction may be performed either under Wolff-Kischner conditions known to those skilled in the art or by activating the relevant Cxe2x95x90O group using an appropriate agent (such as tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower (e.g. C1-6) alkyl alcohol);
(p) for compounds of formula I in which R4 represents halo, substitution of a corresponding compound of formula I in which R4 represents xe2x80x94OH, using an appropriate halogenating agent (e.g. for compounds in which R4 represents fluoro, reaction with (diethylamino)sulfur trifluoride);
(q) for compounds of formula I in which R4 and R5 represent H, A represents xe2x80x94Jxe2x80x94and B represents xe2x80x94N(R25)Zxe2x80x94 (wherein xe2x80x94N(R25) is attached to the carbon atom bearing R4 and R5), reaction of a compound of formula XVIIIA or XVIIIB, 
wherein R1 or R2 (as appropriate) represents R1a, and R1a, R3, R4, R5, R25 Ra to Rh and J are as hereinbefore defined, with a compound of formula XIX, 
wherein R6, G. Z and L2 are as hereinbefore defined, for example at elevated temperature (e.g. 40xc2x0 C. to reflux) in the presence of a suitable organic solvent (e.g. acetonitrile);
(r) for compounds of formula I in which A represents C2 alkylene and R4 and R5 together represent xe2x95x90O, reaction of a compound of formula IIA or IIB, as hereinbefore defined (except that R1 or R2 (as appropriate) does not represent a fragment of formula Ia), with a compound of formula XX, 
wherein B, G and R6 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine, potassium carbonate or tetrabutylammonium hydroxide) and an appropriate organic solvent (e.g. a lower alkyl (e.g. C1-6) alcohol);
(s) for compounds of formula I in which R3 represents H and R2 represents unsubstituted C1-4 alkyl, reaction of a compound of formula XXI, 
wherein R4, R5, R6, Ra to Rh, A, B and G are as hereinbefore defined, with a compound of formula XXII,
R31xe2x80x94NH2xe2x80x83xe2x80x83XXII
wherein R31 represents unsubstituted C1-4 alkyl, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride), for example at between room and reflux temperature, optionally in the presence of an appropriate solvent (e.g. a lower alkyl alcohol such as methanol) and/or a suitable catalyst (e.g. zinc chloride).
(t) for compounds of formula I in which R1 represents xe2x80x94C(O)OR9 and Ra and/or Rb represent C1-4 alkyl, reaction of a corresponding compound of formula I in which R1 represents xe2x80x94C(O)OR9 and Ra and Rb represent H with one or more equivalents of a compound of formula XXIII,
R32xe2x80x94L4xe2x80x83xe2x80x83XXIII
wherein R32 represents C1-4 alkyl and L4 is a leaving group such as halo, alkylsulfate, alkanesulfonate or arenesulfonate, in the presence of an appropriate strong base (e.g. butyllithium), for example at between xe2x88x9280xc2x0 C. and room temperature in the presence of a suitable solvent (e.g. N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene-diamine, THF or mixtures thereof).
(u) for compounds of formula I which are 3-azabicyclo[3.2.1]octane-nitrogen N-oxide derivatives, oxidation of the corresponding 3-azabicyclo[3.2.1]octane nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent (e.g. mCPBA), for example at 0xc2x0 C. in the presence of a suitable organic solvent (e.g. dichloromethane);
(v) for compounds of formula I which are C1-4 alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a 3-azabicyclo[3.2.1]octane nitrogen, reaction, at the 3-azabicyclo[3.2.1]octane nitrogen, of a corresponding compound of formula I with a compound of formula XXIII, as hereinbefore defined, for example at room temperature in the presence of an appropriate organic solvent (e.g. N,N-dimethyl-formamide), followed by purification (using e.g. HPLC) in the presence of a suitable counter-ion provider (e.g. NH4OAc); or
(w) conversion of one R6 substituent to another using techniques well known to those skilled in the art.
Compounds of formula IIA and IIB may be prepared by reaction of a compound of formula XXIV, 
or an N-protected derivative thereof, wherein R3, Ra to Rh are as hereinbefore defined, with a compound of formula m as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (a)), or, in the case of compounds of formula IIA or IIB wherein R1 or R2 (as appropriate) represents a fragment of formula Ia in which A represents CH2 and R4 represents xe2x80x94OH or N(H)R19, wherein R19 is as hereinbefore defined, with a compound of formula VII as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (d)).
Compounds of formula III may be prepared by standard techniques. For example, compounds of formula III in which R28 represents a fragment of formula Ia, wherein:
(1) B represents xe2x80x94Zxe2x80x94Oxe2x80x94 may be prepared by coupling a compound of formula IX, as hereinbefore defined, to a compound of formula XXV,
xe2x80x83L2xe2x80x94Zxe2x80x94C(R4)(R5)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XXV
wherein R4, R5, A, Z and L2 are as hereinbefore defined, and the two L2 groups may be the same or different; or
(2) B represents xe2x80x94C(O)N(R25)xe2x80x94 may be prepared by coupling a compound of formula XXVI, 
wherein G, R6 and R25 are as hereinbefore defined, to a compound of formula XXVII,
L5xe2x80x94C(O)xe2x80x94C(R4)(R)xe2x80x94Axe2x80x94L2xe2x80x83xe2x80x83XXVI
wherein L5 represents a suitable leaving group (e.g. xe2x80x94OH or halo) and R4, R5, A and L2 are as hereinbefore defined;
in both cases, under conditions which are well known to those skilled in the art.
Compounds of formula m in which R1 represents a fragment of formula Ia, wherein A represents C2 alkylene and R4 represents xe2x80x94OR18, in which R18 represents C1-6 alkyl, xe2x80x94E-aryl or xe2x80x94Exe2x80x94Het8 may alternatively be prepared by reaction of a compound of formula XI, as hereinbefore defined, with a compound of formula XXVIII, 
wherein R5, R6, R32, B and G are as hereinbefore defined, for example at between ambient temperature (e.g. 25xc2x0 C.) and reflux temperature in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L2 group (in which L2 is as hereinbefore defined), under conditions that are well known to those skilled in the art.
Compounds of formula IVA and IVB may be prepared by reaction of a compound of formula IIA or IIB, respectively, as hereinbefore defined, with a compound of formula XXIX,
L1xe2x80x94C(O)xe2x80x94L1xe2x80x83xe2x80x83XXIX
wherein L1 is as hereinbefore defined, and in which the two L1 groups may be the same or different, for example at between 0xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. toluene or dichloromethane).
Compounds of formula VII may be prepared in accordance with techniques that are known to those skilled in the art. For example, compounds of formula VII in which:
(1) B represents xe2x80x94CH2Oxe2x80x94 and Y represents O may be prepared by reaction of a compound of formula IX, as hereinbefore defined, with a compound of formula XXX 
wherein R5 and L2 are as hereinbefore defined, for example at elevated temperature (e.g. between 60xc2x0 C. and reflux temperature) in the presence of a suitable base (e.g. potassium carbonate or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene/water), or as otherwise described in the prior art;
(2) R5 represents H, B represents a direct bond, C1-4 alkylene, xe2x80x94Zxe2x80x94N(R25)xe2x80x94, xe2x80x94Zxe2x80x94S(O)nxe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which, in each case, the group Z represents C1-4 alkylene attached to the carbon atom bearing R5) and Y represents O may be prepared by reduction of a compound of formula XXXIA or XXXIB, 
wherein Ba represents xe2x80x94Zaxe2x80x94N(R25), xe2x80x94Zaxe2x80x94S(O)nxe2x80x94 or xe2x80x94Zaxe2x80x94Oxe2x80x94 (in which, in each case, the group Za represents a direct bond or C1-3 alkylene attached to the carbon atom bearing R5), Bb represents a direct bond or C1-4 alkylene, and R6, R25, G and n are as hereinbefore defined, for example at between xe2x88x9215xc2x0 C. and room temperature in the presence of a suitable reducing agent (e.g. NaBH4) and an appropriate organic solvent (e.g. THF), followed by an internal displacement reaction in the resultant intermediate, for example at room temperature in the presence of a suitable base (e.g. potassium carbonate) and an appropriate organic solvent (e.g. acetonitrile);
(3) B represents a direct bond, C1-4 alkylene, xe2x80x94Zxe2x80x94N(R25)xe2x80x94, xe2x80x94Zxe2x80x94S(O)2xe2x80x94 or xe2x80x94Zxe2x80x94Oxe2x80x94 (in which, in each case, the group Z represents C1-4 alkylene attached to the carbon atom bearing R5) and Y represents O may be prepared by oxidation of a compound of formula XXXIIA or XXXIIB, 
wherein R5, R6, Ba, Bb and G are as hereinbefore defined, in the presence of a suitable oxidising agent (e.g. mCPBA), for example by refluxing in the presence of a suitable organic solvent (e.g. dichloromethane); or
(4) B represents xe2x80x94Zxe2x80x94Oxe2x80x94, in which group Z represents C1-4 alkylene attached to the carbon atom bearing R5, and Y represents xe2x80x94N(R19), wherein R19 represents C(O)OR21b or xe2x80x94S(O)2R21c, may be prepared by cyclisation of a compound of formula XXXIII, 
wherein R19b represents xe2x80x94C(O)OR21b or xe2x80x94S(O)2R21c, Zb represents C1-4 alkylene and R5, R6, R21b, R21c, G and L2 are as hereinbefore defined, for example at between 0xc2x0 C. and reflux temperature in the presence of a suitable base (e.g. sodium hydroxide), an appropriate solvent (e.g. dichloromethane, water, or a mixture thereof) and, if necessary, a phase transfer catalyst (such as tetrabutylammonium hydrogensulfate).
Compounds of formula VIIIA and VIIIB may be prepared in a similar fashion to compounds of formula I (see, for example process steps (a) to (d)).
Compounds of formula XIIA and XIIB may be prepared by replacement of the xe2x80x94OH group of a corresponding compound of formula I in which R4 represents xe2x80x94OH with an L2 group under conditions that are known to those skilled in the art.
Compounds of formula XIIIA and XIIIB in which E represents a direct bond may be prepared by reaction of corresponding compounds of formula I in which R4 represents xe2x80x94OH with a compound of formula XXXIV,
R33S(O)2Clxe2x80x83xe2x80x83XXXIV
wherein R33 represents C1-4 alkyl or aryl (which two groups are optionally substituted by one or more substituents selected from C1-4 alkyl, halo and nitro), for example at between xe2x88x9210 and 25xc2x0 C. in the presence of a suitable solvent (e.g. dichloromethane), followed by reaction with a suitable source of the azide ion (e.g. sodium azide), for example at between ambient and reflux temperature in the presence of an appropriate solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. sodium hydrogencarbonate).
Compounds of formula XIIIA and XlIIB may alternatively be prepared by reaction of a compound of formula IIA or IIB, as hereinbefore defined (except that R1 or R2 (as appropriate) does not represent a fragment of formula Ia), with a compound of formula XXXV, 
wherein R5, R6, A, B, E, G and L2 are as hereinbefore defined, for example under analogous conditions to those described hereinbefore for the synthesis of compounds of formula I (process step (a)).
Compounds of formula XVIIIA and XVIIIB may be prepared by removing an optionally substituted benzyloxycarbonyl unit from (i.e. deprotecting) corresponding compounds of formula I in which B represents xe2x80x94N(R25)C(O)OCH2xe2x80x94 and A represents J, wherein R25 and J are as hereinbefore defined, for example under conditions which are known to those skilled in the art.
Compounds of formula XXI may be prepared by reaction of a compound of formula m in which R28 represents a fragment of formula Ia with a compound of formula XXXVI, 
wherein Ra to Rh are as hereinbefore defined, for example under conditions described hereinbefore (process step (a)).
Compounds of formula XXI in which both Ra and Rb represent H may alternatively be prepared by reaction of a compound of formula XXXVII, 
wherein Rc to Rh are as hereinbefore defined, with a compound of formula XXXVIII, 
wherein R4, R5, R6, A, B and G are as hereinbefore defined, in the presence of a formaldehyde (i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution), for example at between room and reflux temperature in the presence of a suitable solvent (e.g. a lower alkyl alcohol such as methanol) and optionally in the presence of an appropriate acid (e.g. acetic acid).
Compounds of formula XXV may be prepared by reaction of a compound of formula XXXVI, as hereinbefore defined, or a N-protected derivative thereof, with a compound of formula XXXIX,
R3xe2x80x94NH2xe2x80x83xe2x80x83XXXIX
or (in the case where R3 represents H) a protected derivative (e.g. N-benzyl) thereof, for example under conditions described hereinbefore for the synthesis of compounds of formula I (process step (s)).
Compounds of formula XXXV may be prepared in analogous fashion to compounds of formula XIIIA and XIIIB (i.e. from the corresponding alcohol).
Compounds of formula XXXVI in which both Ra and Rb represent H may be prepared by reaction of a compound of formula XXXVII with ammonia, or an N-protected derivative thereof (e.g. benzylamine), in the presence of a formaldehyde, for example under conditions described hereinbefore for the synthesis of compounds of formula XX.
Compounds of formulae V, VI, IX, X, XI, XIV, XV, XVI, XVII, XIX, XX, XXII, XXIII, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXIA, XXXIB, XXXIIA, XXXIIB, XXXIII, XXXIV, XXXVII, XXXVIII and XXXIX, and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds defined herein may be converted to other claimed substituents using techniques well known to those skilled in the art. For example, hydroxy may be converted to alkoxy, phenyl may be halogenated to give halophenyl, nitro may be reduced to give amino, amino may be acetylated to give acetylamino, etc.
The skilled person will also appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formulae I. For example, carbonyl may be reduced to hydroxy or alkylene, and hydroxy may be converted to halo.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the process described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenyl-methoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for amidino and guanidino include benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J. W. F. McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1999).
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis.
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Moreover, certain compounds of formula I may act as prodrugs of other compounds of formula I.
All prodrugs of compounds of formula I are included within the scope of the invention.
Some of the intermediates referred to hereinbefore are novel. According to a further aspect of the invention there is thus provided: (a) a compound of formula IIA or IIB, as hereinbefore defined, or a protected derivative thereof; (b) a compound of formula IVA or IVB, as hereinbefore defined, or a protected derivative thereof; (c) a compound of formula VIIIA or VIIIB, as hereinbefore defined, or a protected derivative thereof; (d) a compound of formula XIIA or XIIB, as hereinbefore defined, or a protected derivative thereof; (e) a compound of formula XIIIA or XIIIB, as hereinbefore defined, or a protected derivative thereof; (t) a compound of formula XVIIIA or XVIIIB, as hereinbefore defined, or a protected derivative thereof; (g) a compound of formula XX, as hereinbefore defined (provided that when Ra to Rh all represent H, G represents CH and R6 is absent, then the group xe2x80x94Axe2x80x94C(R4)(R5)xe2x80x94Bxe2x80x94 does not represent unsubstituted ethyl), or a protected derivative thereof; and (h) a compound of formula XXIV, as hereinbefore defined (provided that Ra to Rh do not all represent H), or a protected derivative thereof.
Compounds of formula IIA that may be mentioned include those in which when R3 represents H and R2 represents xe2x80x94C(O)R7a, then R7a does not represent phenyl substituted in the 2-position by C1-6 alkoxy, in the 4-position by xe2x80x94NH2 or xe2x80x94N(H)C(O)R27h (wherein R27h represents C1-6 alkyl), and in the 5-position by halo or xe2x80x94SR26c.
Compounds of formula IIB that may be mentioned include those in which:
(i) when Ra to Rh and R3 all represent H then R1 does not represent C1-3 alkyl optionally substituted by phenyl;
(ii) when R3 represents H then R1 does not represent C1-10 alkyl, or C1-2 alkyl terminated by phenyl or thienyl (which phenyl or thienyl group is optionally substituted by one or two substituents selected from C1-6 alkyl (optionally interrupted by oxygen), C1-4 alkoxy, CF3, halo, nitro, xe2x80x94C(O)OH or xe2x80x94C(O)Oxe2x80x94C1-6 alkyl;
(iii) R1 does not represent C1-2 alkyl substituted by phenyl (which phenyl group bears a para-[2-amino4-(C1-6 alkyl)-pyridin-6-yl] substituent and optionally one or two further substituents independently selected from methyl, methoxy and hydroxy) and optionally by one or two further aryl groups;
(iv) R1 does not represent C2 alkyl terminated by phenyl (which phenyl group bears a para-{2-[1-(2,5-dimethyl-1H-pyrrolyl)-4(C1-6 alkyl)-pyridin-6-yl} substituent and optionally one or two further substituents independently selected from methyl, methoxy and hydroxy); or
(v) R1 does not represent C1 alkyl substituted by phenyl (which phenyl group bears a para-{2-[N-phthaloyl]4-(C1-6 alkyl)-pyridin-6-yl} substituent and a meta-methyl, methoxy or hydroxy group).
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.
Thus, according to a further aspect of the invention there is provided the compounds of the invention for use as pharmaceuticals.
In particular, the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below.
The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.
The compounds of the invention are thus indicated in the treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic events.
In the treatment of arrhythmias, compounds of the invention have been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although compounds of the invention have been found to exhibit class III activity in particular, in the treatment of arrhythmias, their mode(s) of activity is/are not necessarily restricted to this class.
According to a further aspect of the invention, there is provided a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, a pharmaceutically acceptable ion exchanger or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.005 to 10.0 mg/kg body weight at oral administration and about 0.005 to 5.0 mg/kg body weight at parenteral administration.
The compounds of the invention have the advantage that they are effective against cardiac arrhythmias.
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I and/or class IV activity in addition to class III activity)) than, be more potent than, be longer acting than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art.
Test A
Glucocorticoid-treated Mouse Fibroblasts as a Model to Detect Blockers of the Delayed Rectifier K Current
IC50 for K channel blockade was determined using a microtitre plate based screen method, based on membrane potential changes of glucocorticoid-treated mouse fibroblasts. The membrane potential of glucocorticoid-treated mouse fibroblasts was measured using fluorescence of the bisoxonol dye DiBac4(3), which could be reliably detected using a fluorescence laser imaging plate reader (FLIPR). Expression of a delayed rectifier potassium channel was induced in mouse fibroblasts by 24 hours exposure to the glucocorticoide dexamehasone (5 xcexcM). Blockade of these potassium channels depolarised the fibroblasts, resulting in increased fluorescence of DiBac4(3).
Mouse ltk fibroblasts (L-cells) were purchased from American Type Culture Collection (ATCC, Manassa, Va.), and were cultured in Dulbeccos modified eagle medium supplemented with fetal calf serum (5% vol/vol), penicillin (500 units/mL), streptomycin (500 xcexcg/mL) and L-alanine-L-glutamine (0.862 mg/mL). The cells were passaged every 3-4 days using trypsin (0.5 mg/mL in calcium-free phosphate buffered saline, Gibco BRL). Three days prior to experiments, cell-suspension was pipetted out into clear-bottom, black plastic, 96-well plates (Costar) at 25 000 cells/well.
The fluorescence probe DiBac4(3) (DiBac Molecular probes) was used to measure membrane potential. DiBac4(3) maximally absorbs at 488 nM and emits at 513 nM. DiBac4(3) is a bisoxonol, and thus is negatively charged at pH 7. Due to its negative charge, the distribution of DiBac4(3) across the membrane is dependent upon the transmembrane potential: if the cell depolarizes (i.e. the cell interior becomes less negative relative to cell exterior), the DiBac4(3) concentration inside the cell increases, due to electrostatic forces. Once inside the cell, DiBac4(3) molecules can bind to lipids and proteins, which causes an increase in fluorescence emission. Thus, a depolarization will be reflected by an increase in DiBac4(3) fluorescence. The change in DiBac4(3) fluorescence was detected by a FLIPR.
Prior to each experiment, the cells were washed 4 times in phosphate-buffered saline (PBS) to remove all culture media. The cells were then treated with 5 xcexcM DiBac4(3) (in 180 xcexcL of PBS) at 35xc2x0 C. Once a stable fluorescence was reached (usually after 10 min), 20 xcexcL of the test substance was added, using FLIPR""s internal 96 well pipetting system. Fluorescence measurements were then taken every 20 sec for a further 10 min. All experiments were carried out at 35xc2x0 C., due to the high temperature sensitivity of both delayed rectifier potassium channel conductance and DiBac4(3) fluorescence. Test substances were prepared in a second 96 well plate, in. PBS containing 5 xcexcM DiBac4(3). The concentration of substance prepared was 10 times that of the desired concentration in the experiment as an additional 1:10 dilution occurred during addition of substance during the experiment. Dofetilide (10 xcexcM) was used as a positive control, i.e. to determine the maximum increase in fluorescence.
Curve-fitting, used to determine the IC50 values, was performed with the Graphpad Prism program (Graphpad Software Inc., San Diego, Calif.).
Test B
Metabolic Stability of Test Compounds
An in vitro screen was set up to determine the metabolic stability of the compounds of the invention.
The hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co-factor was used. The assay conditions were as follows: S-9 (3 mg/mL), NADPH (0.83 mM), Tris-HCl buffer (50 mM) at pH 7.4 and 10 xcexcM of test compound.
The reaction was started by addition of test compound and terminated after 0, 1, 5, 15 and 30 minutes by raising the pH in the sample to above 10 (NaOH; 1 mM). After solvent extraction, the concentration of test compound was measured against an internal standard by LC (fluorescence/UV detection).
The percentage of test compound remaining after 30 minutes (and thus txc2xd) was calculated and used as a measure for metabolic stability.